An anticipated outcome of the genetic revolution is more individualized treatment and prevention strategies. For the past decade supported by a SCOR in Hypertension (HTN) we have developed a large cohort who has been carefully characterized phenotypically and genotyped for several key candidate genes. We have strong evidence that a number of these genes identify homogeneous subgroups that theoretically should respond to specific therapies. The logical next step is to test these expectations. Our focus has been on the genetic underpinnings of hormonal factors leading to HTN and its associated cardiovascular (CV) risks. From these studies, we have identified several specific intermediate phenotypes of the hypertensive population. Two are the focus of this proposal. Common characteristics are: 1) an abnormality in the regulation of aldosterone (ALDO) secretion when sodium diet is modified and 2) salt sensitive blood pressure (BP). The first intermediate phenotype, comprising 25-30% of hypertensives, is termed non-modulation. Their defect is dysregulation of tissue ANGII production when Na intake is modified in the adrenal and the vasculature. They have abnormalities in renal function but normal renin level. Non-modulators are associated with polymorphic variants of angiotensinogen (ACT) that increases angiotensinogen production-a gain in function mutation- and adipocyte derived leucine aminopeptidase (ALAP) that reduces ANGII degradation- a loss of function mutation. Thereby in two ways non-modulators can increase tissue levels of ANGII. The pathophysiologic features of non-modulation are corrected by administrating an ACE inhibitor. The second intermediate phenotype, only recently identified by our group, is part of the more traditional salt sensitive sub-group: low renin HTN. These individuals have disproportionately increased ALDO levels in contrast to the reduced ALDO levels observed in non-modulators, and are associated with polymorphisms in the [unreadable]-2 adrenergic receptor gene. This intermediate phenotype may comprise a third or more of low renin hypertensives. The overall goal of the present proposal is to expand on these preliminary findings in three ways. First, in non-modulators we will determine the relationship of the two major gene variants to the presence of the metabolic syndrome/insulin resistance-a major feature of non-modulation. Second, for both phenotypes, we will determine the likely mechanism(s) underlying the increased risk of HTN using in vivo and in vitro techniques. Third, for the non-modulators, we will determine the likelihood that therapy directed at these mechanism(s) will be more effective in reducing BP, than will non-specific therapy- pharmacogenetics. Thus, the ultimate outcome of this project is to develop tools for individualized therapy in a substantial fraction of the hypertensive population using mechanistically and genetically driven approaches. [unreadable] [unreadable] [unreadable]